Preparation of (2R, 3R, 4R)-3-hydroxy-2,4,6-trimethylheptanoic acid via enzymatic desymmertization

Article abstract of DOI:10.1016/j.tet.2016.11.050

Synthesis of a unique fatty acyl unit to build the N-terminus of callipeltin A and homophymine B is described. Our approach to access (2R, 3R, 4R)-3-hydroxy-2,4,6-trimethylheptanoic acid uses enzymatic hydrolysis for the desymmetrization of achiral acetate, followed by diastereoselective Roush crotylboration and Wittig olefination for the backbone construction.

Full text of DOI:10.1016/j.tet.2016.11.050

Accepted Manuscript
Preparation of (2R, 3R, 4R)-3-hydroxy-2,4,6-trimethylheptanoic acid via enzymatic
desymmertization
Yoshinori Tokairin, Hiroyuki Konno
PII:
S0040-4020(16)31214-5
10.1016/j.tet.2016.11.050
TET 28264
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 September 2016
Revised Date: 16 November 2016
Accepted Date: 19 November 2016
Please cite this article as: Tokairin Y, Konno H, Preparation of (2R, 3R, 4R)-3-hydroxy-2,4,6-
trimethylheptanoic acid via enzymatic desymmertization, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.11.050.
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Preparation of (2R,3R,4R)-3-hydroxy-2,4,6-
trimethylheptanoic acid via enzymatic
desymmetrization
Yoshinori Tokairin, Hiroyuki Konno*
Graduate School of Science and Engineering, Yamagata University

ACCEPTED MATNeUtraSheCdrRonIPT
3

ACCEPTED MANUSCRIPT
Preparation of (2R, 3R, 4R)-3-hydroxy-2,4,6-trimethylheptanoic acid via enzymatic
desymmertization
Yoshinori Tokairin, Hiroyuki Konnoꢀ
Department of Biochemical Engineering, Graduate School of Science and Engineering,
Yamagata University, Yonezawa, Yamagata 992-8510, Japan
*Corresponding author:
e-mail: konno@yz.yamagata-u.ac.jp
Tel & FAX: +81-(0)-238-26-3131
Abstract: Synthesis of a unique fatty acyl unit to build the N-terminus of callipeltin A
and homophymine
B
is described. Our approach to access (2R, 3R,
4R)-3-hydroxy-2,4,6-trimethylheptanoic acid uses enzymatic hydrolysis for the
desymmetrization of achiral acetate, followed by diastereoselective Roush
crotylboration and Wittig olefination for the backbone construction.
Keywords: cyclicdepsipeptide, fatty acyl unit, enantioselective enzymatic
desymmertization
1. Introduction
Cyclodepsipeptides callipeltin A (1) and homophymine B (2) were isolated from marine
sponges callipelta sp. for 1 and homophymia sp. for 2 by the Zampella group.1,2 These
1

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molecules show potent inhibitory activities against C-C chemokine receptor type 5
(CCR5) which is employed as a coreceptor in HIV infection.1 In addtition, callipeltin A
(1) possesses antifungal activity against Fusarium oxysporum, Helminthosporium
sativum, Phytophtora hevea, and Candida albicans. Homophymine B (2) exhibits IC50
values in the sub nM levels against various tumor cell lines (e.x. PC3, OV3, HL60, and
HepG2).3 The chemical structures of both peptides were determined by the combination
of NMR and MS spectral analysis and Marfey’s4 or the GITC method.5 Several unusual
amino acids are incorporated within the cyclodepsipeptides, which are further modified
by (2R, 3R, 4R)-3-hydroxy-2,4,6-trimethylheptanoic acid (HTH) (3) residues at the
N-terminus. The total synthesis of callipeltin A (1) and homophymine B (2) have never
been reported in the literature, although several synthetic studies of unusual amino acids
and N-terminal fatty acid were revealed by Zampella, Lipton, etc. The characteristic
structure of these peptides and their rare bioactivity motivated us to undertake the total
synthesis of these molecules. Recently, our group achieved the synthesis of callipeltins
B (4) and M (5) and the cyclic fragment of homophymine B (2) utilizing the
combination of solution and solid phase approach.6-8 Our next task is the construction of
both natural peptides 1 and 2. To achieve this, we have already synthesized two unusual
amino acids [(2S, 3S, 4R)-dimethylglutamine (diMeGln)9 and (2R, 3R,
4S)-4-amino-2,3-dihydroxyheptandioic acid (ADH)].10 Therefore, we attempted the
stereoselective synthesis of HTH (3), which is a component of callipeltin A (1) and
homphymine B (2) (Fig. 1).
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OH
H2N
O
NH2
H
N
MeO
HN
N
O
OH
O
H
N
H2N
H2N
NH
NH
OH
O
O
HO
O
O
N
O
H
O
O
NH
O
NH
O
O
N
O
O
OH
O
H
H
N
H
O
N
NH2
NH
N
O
O
O
O
O
HN
N
HN
N
H
H
H
H
N
H
N
H
N
N
OH
O
OH
O
N
N
H
N
O
H
OH
O
OH
O
O
O
O
O
OH
NH2
H2N
OH
O
NH2
Homophymine B (2)
Callipeltin A (1)
OH
OH
H2N
O
H2N
O
H
H
N
N
MeO
O
MeO
HN
N
O
N
O
OH
O
O
O
O
O
HN
O
HO
OH
O
O
O
NH
O
NH
(2R, 3R, 4R)-HTH (3)
H
H
N
O
N
NH2
NH
HO
NH2
NH
O
HN
O
HN
H
H
N
H
H
N
N
N
O
N
H
O
N
H
O
O
OH
OH
Callipeltin M (5)
Callipeltin B (4)
Fig. 1. Callipeltin A (1), Homophymine B (2), HTH (3), Callipeltin B (4), and M (5)
2. Results and discussion
Although the absolute configuration of HTH (3) was determined to be 2R, 3R, 4S, in an
isolation study,1 the Zampella group subsequently revised the stereochemistry of HTH
(3) as 2R, 3R, 4R by comparison between the NMR spectra of isolated HTH (3) and
those of a synthetic one, which was synthesized using Brown’s crotylboration.1,11 Later,
the Lipton group attempted to determine the stereochemistry of HTH (3) by a synthetic
approach.12 Myers alkylation and Brown’s crotylboration as a Lipton’s strategy were
employed to prepare four diastereoisomers of HTH (3). As a result, the spectroscopic
data of all four diastereomers demonstrated the stereochemistries of the natural isomer
to be 2R, 3R, 4R. In addition, this result was supported by Oku et al. Preparation of
HTH-phynylglycine derivative and analyses of its stereochemistry by HPLC were
reported.13 In contrast, Zampella reported isolation of a series of homophymines of
3

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which bind five HTH analogs in 2009.3 As the previous literatures to prepare HTH (3),
there are two elegant synthetic routes by Zampella11 and Lipton12 groups. Zampella
reported the synthesis of HTH (3) derived from (S)-2-methyl-3-hydroxypropionate,
which is expensive as a starting material.11 Lipton adopted Myers alkylation utilized
ephedrine derivatives, and therefore removal process of the auxiliary group is needed to
carry out the chiral materials.12 Thus, we planned a synthetic route applicable for the
synthesis of these analogs starting from cheap material as depicted in Scheme 1. In
order to synthesize various analogs of HTH (3), the homoallylic alcohol 6 was used as
the building block. The isopropyl unit of 3 was introduced by the oxidative cleavage
and Wittig reaction of 6. For construction of two consecutive stereocenters on C-3 and
C-4 of the homoallylic alcohol 6, we noted the crotylboration established by Roush and
co-workers reported in 1987.14 They found that crotylboration of the aldehyde (R)-7
with chiral borate derived from diisopropyl tertrate gave the homoallylic alcohol (2R,
3R, 4S)-6 preferentially.
Although aldehyde (R)-7 derived from (S)-2-methyl-3-hydroxy propionate is
known in the literature,11 it is very expensive and not flexible as a starting material.
Therefore, we decided to produce the remaining stereocenter of aldehyde 7 by a
enantioselective enzymatic approach from a cheap starting material (8). This strategy is
more flexible for the synthesis of different stereoisomers and analogs of HTH (3) and
has advantage for the total synthesis of homophymines compered with previous reports
(Scheme 1).
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3
OH
OTBDPS
2
4
OH
O
OH
3
8
6
H
OTBDPS
HO
OH
2
O
6
Scheme 1. Retrosynthetic analysis of HTH (3)
To prepare HTH (3) based on our strategy as mentioned above, the initial
desymmetrizations of diol 8 and diacetate 10 were attempted by lipase. Previously,
Santaniello et al. reported enzymatic mono-acetylation of diol 8 using PFL
(pseudomonas fluorescens lipase) and vinyl acetate in chloroform to give (-)-9 at a yield
of 40% and 98% e.e.15 Therefore, there is room for improvement in the chemical yield.
On the other hand, Nanda et al. described the enzymatic desymmertization of diacetate
10 utilizing lipase PS-D in phosphate buffer (pH 7.0) to yield the monoacetate (+)-9
(86%, 99% e.e.).16 This is an elegant result, however lipase PS-D is not commercially
available (Scheme 2).
Scheme 2. Chemoenzymatic desymmetrization reaction of 8 and 10
Thus, we firstly started to screen lipases in house with a variety of solvent
5

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systems to give the mono acetylation of diol 8 utilizing 1.0 equiv of vinyl acetate as the
acyl donor. Unfortunately, no satisfactory result was observed, although we attempted
many combinations of various lipases, solvents, reaction times, and temperatures. On
the other hand, the enantiomeric excess of monoacetate 9 was measured by chiral HPLC
analysis after benzoylation and lipase mediated desymmetrization of diacetate 10 to
give (+)-9 was attempted (Table 1). Using lipase M AMANO 10, desymmetrization of
10 in H2O proceeded to give the desired product (+)-9 at a trace amount (entry 1). As
acetic acid generated in this reaction decreased the solvent pH, the reaction mixture was
treated in phosphate buffer pH 7.0 in the presence of lipase M AMANO 10. As a result,
the chemical yield and enantiomeric excess were 50% and 59% e.e. (entry 2). Using
some combinations of lipase catalysts, of which lipase PS AMANO or NOVOZYM 435
were active in preliminary screening, with the phosphate buffers (pH 6.0, 7.0, 8.0), each
reaction proceeded smoothly with moderate enantioselectivities. Treatment of diacetate
10 with NOVOZYM 435 in a phosphate buffer solution (pH 8.0) resulted in 61% yield
and 81% e.e. (entry 3). When using lipase PS AMANO, the reaction in phosphate buffer
solution (pH 7.0) gave 85% e.e. (entries 4-6). In an attempt to adjust the reaction
temperature for further improvement, it was found that lipase PS AMANO in a
phosphate buffer solution of pH 7.0 at 1oC provided satisfactory results (yield = 82%;
e.e. = 95%) although this needed a reaction time for 84h (entry 7).17 It is noted that this
o
reaction did not proceed at -10 C to recover diacetate 10 (entry 8). We have
successfully developed high enantioselective desymmetrization for diacatate 10 to
afford primary alcohol (+)-9 with a common popular and cheap lipase. We found that
lipase PS AMANO works even at 1 oC and this reaction was carried out on a 10 g scale
to deliver the product at a reproducible yield and enantioselectivity. This result
6

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suggested that the process could be applied to other substrates to obtain chiral
compounds (Table 1).18
Table 1. Asymmetric saponification of diacetate 10.
entry enzyme
Solvent
temp. (ºC) time (h) yield (%) e.e. (%)
1
2
3
4
5
6
7
8
lipase M AMANO 10 H2O
r.t.
r.t.
r.t
11
23
2
9.3
50
75
59
81
68
85
81
95
n.d.
lipase M AMANO 10 phosphate buffer pH 7.0
NOVOZYM 435
phosphate buffer pH 8.0
phosphate buffer pH 6.0
phosphate buffer pH 7.0
phosphate buffer pH 8.0
phosphate buffer pH 7.0
61
lipase PS AMANO
lipase PS AMANO
lipase PS AMANO
lipase PS AMANO
lipase PS AMANO
r.t.
r.t.
r.t.
1
5.5
2
36
48
2
61
84
18.5
82
phosphate buffer pH 7.0/acetone =(3/2) -10
trace
Next,
we
prepared
two
optical
isomers
of
3-(tert-butyldiphenylsiloxy)-2-methylpropanol (11) to apply them to the synthesis of
HTH analogs (Scheme 3). The free hydroxyl group in optical active (+)-9 was a
protected BOM group in the treatment with BOMCl in 81% yield. The acetate group
was removed with K2CO3 in MeOH. Protection of the primary alcohol with TBDPSCl
followed by hydrogenation of the BOM group with Pd(OH)2/C catalyst afforded the
TBDPS protected product (R)-11. (S)-11 was synthesized via protection as silyl ether
and deprotection of the acetate group. The optical rotation of our synthetic (R) and
(S)-11, R:[α]D25 = +5.5 and S:[α]D25 = -3.5, were nearly identical to the those in the
literature (lit. R-11:[α]D = +3.9 to +6.3 and lit. S-11:[α]D = -4.3 to -6.0) (Scheme 3).19,20
7

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1) TBDPSCl
imidazole, DMAP
CH2Cl2, 97%
1) BOMCl, DIPEA
CH2Cl2, 81%
2) K2CO3, MeOH, 83%
HO
OAc
TBDPSO
OH
HO
OTBDPS
2) K2CO3
MeOH, 88%
3) TBDPSCl, imidazole
DMAP, CH2Cl2, 71%
4) Pd(OH)2/C, H2
CHCl3, 63%
(+)-9
(S)-11
(R)-11
Scheme 3. Synthesis of both optical isomers of alcohol 11
Finally, we attempted the synthesis of HTH (3). After the oxidation of (R)-11
under the Swern condition, the resulting aldehyde (R)-7 was transformed to (3R, 4R,
5S)-6 and (3S, 4S, 5S)-12 as a 4 to 1 mixture by Roush crotylboration with (E, S, S)-type
chiral borate (82% yields from (R)-11).12 After separation of the mixture by silica gel
column chromatography, the NMR data of (3R, 4R, 5S)-6 and (3S, 4S, 5S)-12 were
identical to those of Roush’s previous report.14 The hydroxyl group of homoallylalcohol
6 was protected as the MOM ether to afford compound 13 in 91% yield. Oxidative
cleavage of olefin 13 followed by Wittig olefination with the condition of
isopropyltriphenylphosphonium iodide/NaHMDS/THF afforded tri-substituted alkene
15 in 58% yield over 2 steps. Deprotection of silyl ether of compound 15 using TBAF
proceeded smoothly to give alcohol 16 in quantitative yield. 17 was derived from 16 by
hydrogenation in the presence of a Pt/C catalyst. After the oxidation of 17 with
TEMPO/NaClO/NaClO2 in CH3CN/pH 7.0 phosphate buffer (1:1), TFA-mediated
deprotection of the MOM group in 18 was carried out to give HTH (3) in 40% yield
over 2 steps. The spectroscopic data of synthetic HTH (3) overlapped with those of the
revised HTH (3) reported by Lipton12 and the HTH fragment of a natural product
(Scheme 4).1
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Scheme 4. Stereoselective synthesis of HTH (3).
3. Conclusion
We achieved efficient asymmetric synthesis of HTH (3), the N-terminus component of
callipeltin A (1) and homophymine B (2). Our synthetic method features
chemoenzymatic desymmetrization to prepare chiral alcohol (+)-9 and Roush
crotylboration as the key steps. This method is flexible and applicable to other
analogues.
4. Experimental
4.1. General information.
Optical rotations were determined with a JASCO DIP-371 polarimeter at the sodium D
line. IR spectra of sample were obtained as films with a JASCO FT-IR 460 spectrometer.
1H (400 and 500 MHz) and 13C NMR (100 and 125 MHz) were determined on a
JNM-ECX400, JNM-ECX500. Chemical shifts are reported in ppm with reference to
9

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tetramethylsilane [1H NMR: CDCl3 (0.00)], or solvent signals [1H NMR: CDCl3 (7.26),
D2O (4.79), MeOH-d4 (3.30); 13C NMR: CDCl3 (77.16), MeOH-d4 (50.05)].
Low-resolution mass spectra were recorded on a JEOL AccuTOF JMS-T100LC
(ESI-MS). Analytical TLC was performed on Merck Silica gel 60F254. Crude products
were purified by columm chromatography on Silica Gel 60N [Kanto, particle size,
(spherical, neutral) 63-210 µm or 100-200 µm. HPLC system (monitored at 254 nm)
equipped with DAICEL CHIRALCEL OD-H (0.46 cm φ × 25 cm) using 0.3%
2-propanol/Hexane.
4.2.
(R)-3-Hydroxy-2-methylpropylacetate
(9):
To
a
solution
of
1,3-diacetoxy-2-methylpropane (10) (8.53 g, 49.0 mmol) in 0.5 M phosphate buffer pH
7.0 (200 ml) at 1 °C was added lipase PS Amano (200 mg), and the reaction was stirring
for 84h. After lipase was removed by filtration, mother liquid was extracted with AcOEt.
The organic layer was washed with brine and NaHCO3 aq., and dried over magunesium
sulfate, and evaporated in vacuo. The residue was purified by column chromatography
(Hexane:AcOEt = 3:1) to give compound 9 (5.33 g, 40.3 mmol, 82%, 95% e.e.) as a
colorless oil. [α]D29 +5.5 (c 1.00, CHCl3), {lit15 [α]D20 +10.0 (c 1.00, CHCl3)}. IR (film)
νmax cm-1: 3447, 2964, 2882, 2360, 2341, 1738, 1469, 1369, 1244, 1038, 992, 950, 907,
607, 439 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.95 (3H, d, J = 7.0 Hz), 2.02-1.93 (1H,
m), 2.03 (1H, br), 2.07 (3H, s), 3.53-3.47 (2H, m), 4.04 (1H, dd, J = 11.5, 6.5 Hz), 4.11
(1H, dd, J = 11.5, 5.0 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.4, 20.7, 35.2, 64.0,
66.2, 171.6 ppm. HRMS-EI: m/z [M-H]- calcd for C6H11O3: 131.0708; found: 131.0731.
4.3. (R)-3-(tert-Butyldiphenylsiloxy)-2-methylpropanol (R)-11: To a solution of
10

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(R)-3-hydroxy-2-methylpropylacetate (4) (2.98 g, 22.5 mmol) in CH2Cl2 at 1 °C was
added DIPEA (67.5 mmol, 11.8 ml) and BOMCl (33.8 mmol, 4.64 ml), and the reaction
was stirring for 10h. The mixture was quenched with water and aqueous layer extracted
with CH2Cl2. The organic layer was washed with brine, and dried over magunesium
sulfate, and evaporated in vacuo. The residue was purified by column chromatography
(Hexane:AcOEt = 6:1) to give (R)-3-benzyloxymethoxy-2-methylpropylacetate (4.60 g,
26
18.2 mmol, 81%) as a colorless oil. [α]D -0.20 (c 1.00, CHCl3). IR (film) νmax cm-1:
2960, 2880, 1738, 1497, 1455, 1379, 1366, 1243, 1174, 1111, 1043, 738, 699, 455 cm-1.
1H NMR (500 MHz, CDCl3): δ = 0.99 (3H, d, J = 6.5 Hz), 2.03 (3H, s), 2.07-2.14 (1H,
m), 3.48-3.54 (2H, m), 4.01 (1H, dd, J = 11.0, 6.5 Hz), 4.08 (1H, dd, J = 11.5, 6.5 Hz),
13
4.59 (2H, s), 4.74 (2H, s), 7.27-7.31 (1H, m), 7.34-7.35 (4H, m) ppm. C NMR (125
MHz, CDCl3): δ = 14.2, 21.0, 33.3, 66.4, 69.4, 69.8, 94.8, 127.8, 127.9, 128.5, 137.9,
171.2 ppm. HRMS-ESI: m/z [M+Na]+ calcd for C14H20O4Na: 275.1259; found:
275.1257. To a solution of (R)-3-benzyloxymethoxy-2-methylpropylacetate (1.50 g,
5.95 mmol) in MeOH at 0°C was added K2CO3 (2.98 mmol, 412 mg), and the reaction
was stirring for 8h. The solvent was removed under reduced pressure and the crude
residue was added to water. The aqueous layer extracted with AcOEt. The organic layer
was washed with brine, and dried over magunesium sulfate, and evaporated in vacuo.
The residue was purified by column chromatography (Hexane:AcOEt = 3:1) to give
benzyloxymethoxy-2-methylpropanol (1.04 g, 4.95 mmol, 83%) as a colorless oil.
25
[α]D -7.3 (c 1.00, CHCl3). IR (film) νmax cm-1: 3421, 2927, 2878, 2064, 1953, 1869,
1
1810, 1739, 1646, 1497, 1455, 1379, 1170, 1042, 737, 698 cm-1. H NMR (500 MHz,
CDCl3): δ = 0.92 (3H, d, J = 7.0 Hz), 1.97-2.04 (1H, m), 2.33 (1H, br), 3.54 (1H, dd, J =
9.5, 8.0 Hz), 3.59-3.60 (2H, m), 3.64 (1H, dd, J = 9.5, 5.0 Hz), 4.60 (2H, s), 4.75 (2H, s),
11

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7.28-7.32 (1H, m), 7.35-7.36 (4H, m) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.7, 35.8,
67.1, 69.6, 72.3, 94.9, 127.9, 128.0, 128.6, 137.8 ppm. HRMS-ESI: m/z [M+Na]+ calcd
for
C12H18O3Na:
233.1154;
found:
233.1153.
To
a
solution
of
(S)-3-benzyloxymethoxy-2-methylpropanol (1.04 g, 4.95 mmol) in CH2Cl2 at 0°C was
added imidazole (14.9 mmol, 1.01g), DMAP (cat.), and TBDPSCl (5.45 mmol, 1.42 ml)
and the reaction was stirring for 12h. The mixture was quenched with water and
aqueous layer extracted with CH2Cl2. The organic layer was washed with brine, and
dried over magunesium sulfate, and evaporated in vacuo. The residue was purified by
column
chromatography
(Hexane:AcOEt
=
10:1)
to
give
(R)-3-benzyloxymethoxy-1-(tert-butyldiphenylsiloxy)-2-methylpropane (1.58 g, 3.52
mmol, 71%) as a colorless oil. [α]D23 +4.4 (c 1.00, CHCl3). IR (film) νmax cm-1: 3069,
2957, 2930, 2857, 1959, 1888, 1823, 1774, 1589, 1471, 1428, 1390, 1157, 1111, 1047,
823, 738, 700, 613 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.99 (3H, d, J = 6.5 Hz), 1.07
(9H, s), 1.98-2.04 (1H, m), 3.54 (1H, dd, J = 10.0, 6.5 Hz), 3.61-3.68 (3H, m), 4.59 (2H,
s), 4.75 (2H, s), 7.27-7.31 (1H, m), 7.33-7.35 (4H, m), 7.37-7.45 (6H, m), 7.67-7.69 (4H,
m) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.2, 19.4, 27.0, 36.4, 65.9, 69.3, 70.3, 94.9,
127.4, 127.7, 128.0, 128.5, 129.7, 134.0, 135.7, 138.1 ppm. HRMS-ESI: m/z [M+Na]+
calcd for C28H36O3SiNa: 471.2331; found: 471.2361. To
a
solution of
(R)-3-benzyloxymethoxy-1-(tert-butyldiphenylsiloxy)-2-methylpropane (1.58 g, 3.52
mmol) in CHCl3 was added Pd(OH)2/C (cat.) and the suspension was stirring for 4h.
The reaction mixture was filtered and evaporated in vacuo. The residue was purified by
column
chromatography
(Hexane:AcOEt
=
6:1)
to
give
(R)-3-(tert-Butyldiphenylsiloxy)-2-methylpropanol {(R)-11} (729 mg, 2.22 mmol, 63%)
26
as a colorless oil. [α]D +5.5 (c 1.00, CHCl3). IR (film) νmax cm-1: 3358, 3071, 2958,
12

ACCEPTED MANUSCRIPT
2930, 2857, 1959, 1892, 1824, 1589, 1471, 1427, 1390, 1361, 1261, 1187, 1111, 1038,
938, 823, 801, 739, 701, 665, 613 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.82 (3H, d, J
= 6.5 Hz), 1.05 (9H, s), 1.96-2.02 (1H, m), 2.54-2.55 (1H, br), 3.59 (1H, dd, J = 10.5,
8.5 Hz), 3.67 (2H, t, J = 6.0 Hz), 3.72 (1H, dd, J = 9.5, 4.0 Hz), 7.38-7.45 (6H, m),
13
7.66-7.68 (4H, m) ppm. C NMR (125 MHz, CDCl3): δ = 13.3, 19.2, 26.9, 37.4, 67.8,
68.8, 127.5, 129.8, 133.2, 135.6 ppm. HRMS-ESI: m/z [M+Na]+ calcd for
C20H28O2SiNa: 351.1756; found: 351.1753. Optical purity was determined as 95% ee by
HPLC using chiral column {DAICEL CHIRALCEL OD-H (0.46 cm φ × 25 cm), elution
with 0.3% 2-propanol/Hexane} after conversion into the corresponding benzoate (Rt=
7.95 min).
4.4. (S)-3-(tert-Butyldiphenylsiloxy)-2-methylpropanol (S)-11: To a solution of
(S)-3-benzyloxymethoxy-2-methylpropanol (3.09 g, 23.4 mmol) in CH2Cl2 at 0°C was
added imidazole (46.8 mmol, 3.19 g), DMAP (cat.), and TBDPSCl (35.1 mmol, 9.13
ml) and the reaction was stirring for 12h. The mixture was quenched with water and
aqueous layer extracted with CH2Cl2. The organic layer was washed with brine, dried
over magnesium sulfate, and evaporated in vacuo. The residue was purified by column
chromatography
(Hexane:AcOEt
=
20:1)
to
give
(S)-3-acetoxy-1-(tert-butyldiphenylsiloxy)-2-methylpropane (8.46 g, 22.8 mmol, 97%)
26
1
as a colorless oil. [α]D -0.5 (c 1.00, CHCl3). H NMR (500 MHz, CDCl3): δ = 0.95
(3H, d, J = 7.0 Hz), 1.04 (9H, s), 2.00 (3H, m), 3.54-3.61 (2H, m), 4.04 (2H, dd, J =
11.0, 6.0 Hz), 4.11 (2H, dd, J = 11.0, 6.0 Hz), 7.36-7.43 (6H, m), 7.65 (2H, d, J = 7.0
Hz) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.7, 19.4, 21.0, 27.0, 35.3, 65.3, 66.2,
127.7,
129.7,
133.7,
135.7,
171.2
ppm.
To
a
solution
of
13

ACCEPTED MANUSCRIPT
(S)-3-acetoxy-2-methylpropylacetate (2.03 g, 5.48 mmol) in MeOH was added K2CO3
(2.74 mmol, 379 mg) and the reaction was stirring for 10h. The solvent was removed
under reduced pressure and the crude residue was added to water. The aqueous layer
extracted with ether. The organic layer was washed with brine, dried over magnesium
sulfate, and evaporated in vacuo. The residue was purified by column chromatography
(Hexane:AcOEt = 3:1) to give (S)-3-(tert-Butyldiphenylsiloxy)-2-methylpropanol
25
{(S)-11} (1.68 g, 5.11 mmol, 93%) as a colorless oil. [α]D -3.5 (c 1.00, CHCl3). The
spectroscopic data of S-11 were identical to those of R-11.
4.5. (3R, 4R, 5S)-6-(tert-Butyldiphenylsiloxy)-4-hydroxy-3,5-dimethylhexanene (6)
and (3S, 4S, 5S)-6-(tert-Butyldiphenylsiloxy)-4-hydroxy-3,5-dimethylhexanene (12):
Oxalyl chloride (20 mmol, 1.72 ml) was added in dry CH2Cl2 at -78°C. DMSO (40.0
mmol, 2.84 ml) was added to the solution. After 10 min, alcohol 11 (3.29 g, 10.0 mmol)
was added dissolving in dry CH2Cl2. The reaction mixture was kept at same temperature
for 10 min. Then Et3N (60.0 mmol, 8.39 ml) was added to the solution and it was
allowed to warm room temperature. After 15 min, The mixture was quenched with
water and aqueous layer extracted with CH2Cl2. The organic layer was washed with
brine, and dried over magnesium sulfate, and evaporated in vacuo to give aldehyde 7 as
1
a colorless oil. 7: H NMR (500 MHz, CDCl3): δ = 1.03 (9H, s), 1.09 (3H, d, J = 7.5
Hz), 2.53-2.60 (1H, m), 3.84 (1H, dd, J = 11.0, 7.0 Hz), 3.89 (1H, dd, J = 10.5, 5.5 Hz),
7.37-7.45 (6H, m), 7.63-7.64 (4H, m), 9.76 (1H, d, J = 1.5 Hz) ppm. To a solution of
(2E,
4S,
5S)-1,3,2-dioxaborolane-4,5-dicarboxylic
acid
2-butenyl-4,5-bis(1-methylethyl) ester in toluene was added MS4Å (3.0 g) in -78°C.
Aldehyde 6 was added dissolving in toluene slowly. After 2.5h, The reaction was
14

ACCEPTED MANUSCRIPT
quenched with 1M NaOH aq. and filtered. The mother liquid was extracted with ether.
The organic layer was washed with brine, dried over magnesium sulfate, and evaporated
in vacuo. The crude product was purified by column chromatography (Hexane) to give
12 (0.67 g, 1.75 mmol, 18%) and 6 (2.48 g, 6.48 mmol, 65%) as a colorless oil. 6:
24
20
[α]D +15.8 (c 2.00, CHCl3), {lit14c [α]D +26.2 (c 0.80, CHCl3)}. IR (film) νmax
cm-1: 3499, 3071, 2960, 2931, 2857, 2359, 1960, 1889, 1826, 1736, 1637, 1589, 1471,
1
1427, 1325, 1281, 1111, 1005, 912, 822, 740, 701, 613 cm-1. H NMR (500 MHz,
CDCl3): δ = 0.80 (3H, d, J = 6.5 Hz), 1.05 (9H, s), 1.11 (3H, d, J = 7.0 Hz), 1.80-1.87
(1H, m), 2.34-2.40 (1H, m), 3.43 (1H, dt, J = 8.0, 3.5 Hz), 3.53, (1H, d, J = 3.5 Hz),
3.68 (1H, dd, J = 10.5, 7.5 Hz), 3.73 (1H, dd, J = 10.0, 4.5 Hz), 5.04-5.09 (2H, m), 5.94
(1H, ddd, J = 17.5, 11.0, 8.5 Hz), 7.39-7.46 (6H, m), 7.67-7.69 (4H, m) ppm. 13C NMR
(125 MHz, CDCl3): δ = 13.7, 17.9, 19.2, 26.9, 37.9, 41.3, 69.1, 79.9, 115.3, 127.9,
130.0, 133.0, 135.7, 140.0 ppm. HRMS-ESI: m/z [M+Na]+ calcd for C24H34O2SiNa:
405.2226; found: 405.2243. 12: [α]D +5.8 (c 1.00, CHCl3) ,{lit14c [α]D20 +4.9 (c 2.80,
25
CHCl3)}. IR (film) νmax cm-1: 3507, 3071, 2961, 2930, 2857, 1959, 1889, 1824, 1638,
1
1589, 1472, 1428, 1390, 1111, 997, 914, 823, 739, 701 cm-1. H NMR (500 MHz,
CDCl3): δ = 0.95 (6H, d, J = 7.0 Hz), 1.06 (9H, s), 1.81-1.84 (1H, m), 2.26-2.30 (1H, m),
2.44 (1H, d, J = 2.5 Hz), 3.59 (1H, dt, J = 8.5, 2.0 Hz), 3.72 (2H, d, J = 5.0 Hz),
5.08-5.12 (2H, m), 5.82 (1H, ddd, J = 19.0, 10.5, 8.0 Hz), 7.37-7.45 (6H, m), 7.66-7.69
13
(4H, m) ppm. C NMR (125 MHz, CDCl3): δ = 9.7, 16.9, 19.4, 27.0, 36.8, 41.9, 68.6,
76.3, 115.5, 127.8, 129.8, 133.3, 135.7, 142.0 ppm. HRMS-ESI: m/z [M+Na]+ calcd for
C24H34O2SiNa: 405.2226; found: 405.2238.
4.6. (3R, 4R, 5S)-6-(tert-Butyldiphenylsiloxy)-4-methoxymethoxy-3,5-dimethyl
15

ACCEPTED MANUSCRIPT
hexanene (13): To a solution of 6 (428 mg, 1.12 mmol) in CH2Cl2 at 0°C was added
DIPEA (11.2 mmol, 1.92 ml) and MOMCl (5.60 mmol, 0.421 ml), and the reaction was
stirring for 3d. The reaction was quenched with water and aqueous layer was extracted
with CH2Cl2. The organic layer was washed with brine, and dried over magnesium
sulfate, and evaporated in vacuo. The residue was purified by column chromatography
22
(Hexane) to give compound 13 (0.435 mg, 1.02 mmol, 91%) as a colorless oil. [α]D
+2.3 (c 1.00, CHCl3). IR (film) νmax cm-1: 3071, 2960, 2931, 2889, 2857, 2359, 2342,
1958, 1889, 1825, 1738, 1639, 1589, 1472, 1428, 1389, 1361, 1308, 1146, 1111, 1034,
916, 823, 739, 701, 613 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.98 (3H, d, J = 7.0 Hz),
1.05 (3H, d, J = 7.5 Hz), 1.07 (9H, s), 1.84-1.90 (1H, m), 2.41-2.47 (1H, m), 3.26 (3H,
s), 3.33 (1H, dd, J = 7.5, 4.0 Hz), 3.62 (1H, dd, J = 10.0, 7.0 Hz), 3.72 (1H, dd, J = 10.0,
4.5 Hz), 4.53 (1H, d, J = 6.5 Hz), 4.62 (1H, d, J = 7.0 Hz), 4.97-4.98 (1H, m), 5.00, (1H,
s), 5.82 (1H, ddd, J = 18.5, 10.0, 8.0 Hz), 7.35-7.43 (6H, m), 7.65-7.68 (4H, m) ppm.
13C NMR (125 MHz, CDCl3): δ = 14.6, 18.1, 19.4, 27.1, 38.9, 40.4, 56.0, 65.7, 85.2,
98.4, 114.6, 127.7, 129.0, 134.0, 135.8, 140.7 ppm. HRMS-ESI: m/z [M+Na]+ calcd for
C26H38O3SiNa: 449.2488; found: 449.2481.
4.7. (4R, 5R, 6S)-7-(tert-Butyldiphenylsiloxy)-5-methoxymethoxy-2,4,6-trimethyl-2-
heptene (15): Ozone was bubbled through a solution of alkene 13 (807 mg, 1.89 mmol)
in MeOH at -78°C. After 11h, Zn (28.4 mmol, 1.86 g) and AcOH (3.78 mmol, 0.216 ml)
were added to the reaction mixture. The suspension was filtered and evaporated in
vacuo. The crude product was purified by column chromatography (Hexane:AcOEt =
1
40:1) to give aldehyde 14 (662 mg, 1.54 mmol, 63%) as a colorless oil. 14: H NMR
(400 MHz, CDCl3): δ = 0.92 (3H, d, J = 7.2 Hz), 1.05 (9H, s), 1.11 (3H, d, J = 7.2 Hz),
16

ACCEPTED MANUSCRIPT
1.96-2.02 (1H, m), 2.69-2.72 (1H, m), 3.27 (3H, s), 3.61-3.69 (2H, m), 3.82 (1H, dd, J =
6.4, 4.0 Hz), 4.54 (1H, d, J = 6.8 Hz), 4.64 (1H, d, J = 6.8 Hz), 7.35-7.39 (6H, m),
7.62-7.65 (4H, m), 9.72 (1H, d, J = 2.0 Hz) ppm. To a solution of
isopropyltriphenylphosphonium iodide (4.62 mmol, 2.00 g) in THF at -78°C was added
1.9 M NaHMDS/THF (4.62 mmol, 2.43 ml) over 20 min. The reaction mixture was
allowed to warm room temperature, and aldehyde 14 was added dissolving in THF.
After 1.5h, the mixture was quenched with NH4Cl aq. and water at 0°C. The aqueous
layer was extracted with AcOEt. The organic solvent was washed brine and dried over
magnesium sulfate and evaporated in vacuo. The residue was purified by column
chromatography (Hexane:AcOEt = 40:1) to give compound 15 (507 mg, 1.11 mmol,
72%) as a colorless oil. [α]D -4.7 (c 0.085, CHCl3). IR (film) νmax cm-1: 3071, 2959,
26
2927, 2856, 2359, 1956, 1888, 1827, 1733, 1471, 1428, 1362, 1260, 1147, 1111, 1035,
920, 739, 701 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.93 (3H, d, J = 7.0 Hz), 0.95 (3H,
d, J = 6.5 Hz), 1.06 (9H, s), 1.55 (3H, overlapped), 1.66 (3H, s), 1.81-1.86 (1H, m),
2.55-2.60 (1H, m), 3.26 (3H, m), 3.30 (1H, dd, J = 7.5, 4.0 Hz), 3.59 (1H, dd, J = 10.0,
6.5 Hz), 3.71 (1H, dd, J = 10.5, 4.5 Hz), 4.54 (1H, d, J = 7.0 Hz), 4.61 (1H, d, J = 7.0
Hz), 5.10 (1H, d, J = 9.5 Hz), 7.28-7.42 (6H, m), 7.64-7.67 (4H, m) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.6, 18.0, 18.9, 19.4, 26.0, 27.1, 29.8, 34.9, 39.4, 56.0, 65.8,
85.7, 98.4, 126.7, 127.6, 129.6, 134.0, 135.8 ppm. HRMS-ESI: m/z [M+Na]+ calcd for
C28H42O3SiNa: 477.2801; found: 477.2767.
4.8. (4R, 5R, 6S)-7-Hydroxy-5-methoxymethoxy-2,4,6-trimethyl-2-heptene (16): To
a solution of 15 (507 mg, 1.11 mmol) in THF at 0°C added 1.0 M TBAF/THF solution
(2 ml). After 12h, the mixture was quenched with H2O. The aqueous layer was extracted
17

ACCEPTED MANUSCRIPT
with AcOEt. The combined organic layer was washed with NH4Cl aq. and dried over
magnesium sulfate and evaporated in vacuo. The residue was purified by column
chromatography (Hexane:AcOEt = 10:1) to give compound 16 (237 mg, 1.10 mmol,
26
99%) as a colorless oil. [α]D -67.2 (c 0.50, CHCl3). IR (film) νmax cm-1: 3447, 2963,
2927, 2359, 2341, 1732, 1716, 1671, 1451, 1376, 1213, 1146, 1096, 1034, 983, 920,
1
849 cm-1. H NMR (500 MHz, CDCl3): δ = 0.95 (3H, d, J = 7.0 Hz), 0.98 (3H, d, J =
6.5 Hz), 1.61 (3H, d, J = 1.0 Hz), 1.69 (3H, d, J = 1.5 Hz), 1.70-1.76 (1H, m), 2.60-2.67
(1H, m), 2.92 (1H, br), 3.30 (1H, dd, J = 8.0, 3.5 Hz), 3.43 (3H, s), 3.47 (1H, dd, J =
11.5, 3.5 Hz), 3.84 (1H, dd, J = 11.5, 3.5 Hz), 4.67-4.71 (2H, m), 5.09 (1H, dt, J = 10.0,
1.5 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ = 15.1, 18.6, 25.9, 35.4, 38.1, 65.1, 87.5,
99.2, 125.5, 131.8 ppm. HRMS-ESI: m/z [M+Na]+ calcd for C12H24O3Na: 239.1623;
found: 239.1631.
4.9. (2S, 3R, 4R)-3-Methoxymethoxy-2,4,6-trimethyl-1-heptanol (17): To a solution
of 16 (60.8 mg, 0.278 mmol) in MeOH was added Pt/C (cat.) and the suspension was
stirring for 2h under H2 atmosphere. The reaction mixture was filtered and evaporated to
25
give compound 17 (51.3 mg, 0.235 mmol, 85%) as a colorless oil. [α]D -35.5 (c 0.40,
CHCl3). IR (film) νmax cm-1: 3435, 2957, 2929, 1466, 1383, 1367, 1212, 1142, 1093,
1
1036, 987, 919, 665, 455, 439 cm-1. H NMR (500 MHz, CDCl3): δ = 0.83 (3H, d, J =
7.0 Hz), 0.91 (3H, d, J = 7.0 Hz), 0.95 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 7.5 Hz),
1.08-1.20 (2H, m), 1.08-1.20 (2H, m), 1.58-1.66 (1H, m), 1.75-1.81 (1H, m), 1.83-1.88
(1H, m), 3.31 (1H, dd, J = 8.5, 3.0 Hz), 3.43 (3H, s), 3.52 (1H, dd, J = 11.5, 4.0 Hz),
3.84 (1H, dd, J = 11.5, 3.5 Hz), 4.67-4.71 (2H, m) ppm. 13C NMR (125 MHz, CDCl3): δ
= 15.4, 17.3, 21.4, 24.3, 25.4, 33.0, 36.9, 39.9, 56.3, 65.5, 88.2, 99.0 ppm. HRMS-ESI:
18

ACCEPTED MANUSCRIPT
m/z [M+Na]+ calcd for C12H26O3Na: 241.1780; found: 241.1762.
4.10. (2R, 3R, 4R)-3-Methoxymethoxy-2,4,6-trimethylheptanoic acid (18): To a
solution of alcohol 17 (7.9 mg, 36.2 µmol) in CH3CN was added TEMPO (cat.), 0.5 M
phosphate buffer pH 7.0, NaClO2 (72.4 µmol, 6.6 mg), and NaClO aq. (2 ml). After 2h,
2M HCl aq. was added to the mixture (pH = 1.0). The aqueous layer was extracted with
AcOEt. The AcOEt layer was extracted with 1M NaOH aq., and 2M HCl aq. was added
to the aqueous layer again (pH = 1.0). The organic solvent was washed with brine and
dried over magnesium sulfate and evaporated to give the compound 18 (5.3 mg, 22.8
µmol, 62%) as a colorless oil. [α]D26 + 9.1 (c 0.27, CHCl3). IR (film) νmax cm-1: 3178,
2956, 2930, 2359, 2341, 1711, 1463, 1418, 1382, 1367, 1297, 1244, 1215, 1141, 1096,
1
1033, 976, 936, 920, 840, 666, 453, 405 cm-1. H NMR (500 MHz, CDCl3): δ = 0.83
(3H, d, J = 7.0 Hz), 0.91 (3H, d, J = 6.0 Hz), 0.94 (3H, d, J = 6.5 Hz), 1.11-1.20 (1H, m),
1.21 (3H, d, J = 6.5 Hz), 1.58-1.65 (1H, m), 2.76-2.82 (1H, m), 3.38 (3H, s), 3.55 (1H,
13
dd, J = 6.0, 4.0 Hz), 4.66-4.70 (2H, m) ppm. C NMR (100 MHz, CDCl3): δ = 14.6,
16.0, 21.4, 24.0, 25.2, 32.8, 40.6, 42.4, 56.1, 85.6, 97.9, 179.6 ppm. HRMS-ESI: m/z
[M+Na]+ calcd for C12H24O4Na: 255.1572; found: 255.1599.
4.11. (2R, 3R, 4R)-3-Hydroxy-2,4,6-trimethylheptanoic acid [HTH] (3): To a
solution of 18 (5.3 mg, 22.8 µmol) in CH2Cl2 was added TFA (0.5 ml). After 10h, the
mixture was evaporated, and ether and 1M NaOH aq. was added to the residue. Then
2M HCl aq. was added to water phase (pH = 1.0) and water layer was extracted with
AcOEt. The combine organic phase was washed with brine and dried over magnesium
sulfate and evaporated to give HTH (3) (2.8 mg, 14.9 µmol, 65%) as a colorless oil.
19

ACCEPTED MANUSCRIPT
[α]D25 + 15.7 (c 0.14, CHCl3), {lit12 [α]D25 + 14.9 (c 0.4, CHCl3)}. IR (film) νmax cm-1:
3424, 2957, 2927, 2360, 1713, 1462, 1384, 1289, 1261, 1202, 1133, 1082, 987, 963,
1
666 cm-1. H NMR (500 MHz, CDCl3): δ = 0.84 (3H, d, J = 6.0 Hz), 0.92 (3H, d, J =
6.5 Hz), 0.95 (3H, d, J = 6.5 Hz), 1.10-1.16 (1H, m), 1.25 (3H, d, J = 7.0 Hz), 1.64-1.70
(2H, m), 2.73 (dq, J = 7.5, 7.5 Hz), 3.48 (1H, dd, J = 6.0, 5.0 Hz) ppm. 13C NMR (125
MHz, CDCl3): δ = 14.7, 16.6, 21.2, 24.3, 25.1, 33.4, 39.4, 42.1, 78.2, 180.6 ppm.
HRMS-ESI: m/z [M+Na]+ calcd for C10H20O3Na: 211.1310; found: 211.1311.
Acknowledgement
This work was supported in part by a Grant-in-Aid from the Japan Society for the
Promotion of the Science (240145) to H.K. Y.T. is grateful to the Japan Society for the
Promotion of Science Fellowships for young scientists (00465).
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